User:Alisha, Deepa, Pamiz/Sandbox 1: Difference between revisions

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== Esomeprazole Mechanism ==

Esomeprazole is protonated twice within the acidic environment, and forms the active inhibitor—achiral sulfenamide at pKa of 1.0 [15]. [[Image:mechanism of inhibition.jpg|500px|right|thumb| '''Activation of Esomeprazole to sulfonamide [7].''' R1=OCH3, R2=CH3, R3=CH3, R4=CH3, X=CH, Bz=benzimidazole, Py=pyridine[7]. Mechanism: (1) protonation of Py, (2) protonation of Bz, (3) intramolecular rearrangement of BzH+-Py, forms sulfenic acid (4) dehydration to form sulfenamide (5) disulfide bond formation between enzyme Cys residues and ~~sulfenamide~~. ]] The mechanism by which Esomeprazole is converted is as follows: the pyridine ring is first protonated (1), which alters the configuration of the enzyme to the E2 form. Esomeprazole accumulates in the stimulated secretory canaliculus of the parietal cell. As H+ is being transported by the ATPase, the second H+ is added onto the benzimidazole moiety (2) [7]. The bis-protonated forms are in equilibrium with the unprotonated pyridine and protonated benzimidazole rings [7].The protonated benzimidazole ring reacts with the unprotonated pyridine moiety enabling intramolecular rearrangement, resulting in a tetracyclic sulfenic acid (3) [7]. The sulfenic acid is dehydrated to form an active sulfenamide; both are thiophilic agents that are permanently cationic and membrane impermeable (4) [16]. Sulfenamide can form disulfide bonds with Cys813 residues located between TM5 and TM6 loops and a Cys892 located between the TM7 and TM8 loops on the α subunit of the H+/K+-ATPase(5) [17].

Esomeprazole is protonated twice within the acidic environment, and forms the active inhibitor—achiral sulfenamide at pKa of 1.0 [15]. [[Image:mechanism of inhibition.jpg|500px|right|thumb| '''Activation of Esomeprazole to sulfonamide [7].''' R1=OCH3, R2=CH3, R3=CH3, R4=CH3, X=CH, Bz=benzimidazole, Py=pyridine[7]. Mechanism: (1) protonation of Py, (2) protonation of Bz, (3) intramolecular rearrangement of BzH+-Py, forms sulfenic acid (4) dehydration to form sulfenamide (5) disulfide bond formation between enzyme Cys residues and sulfonamide [7]. ]] The mechanism by which Esomeprazole is converted is as follows: the pyridine ring is first protonated (1), which alters the configuration of the enzyme to the E2 form. Esomeprazole accumulates in the stimulated secretory canaliculus of the parietal cell. As H+ is being transported by the ATPase, the second H+ is added onto the benzimidazole moiety (2) [7]. The bis-protonated forms are in equilibrium with the unprotonated pyridine and protonated benzimidazole rings [7].The protonated benzimidazole ring reacts with the unprotonated pyridine moiety enabling intramolecular rearrangement, resulting in a tetracyclic sulfenic acid (3) [7]. The sulfenic acid is dehydrated to form an active sulfenamide; both are thiophilic agents that are permanently cationic and membrane impermeable (4) [16]. Sulfenamide can form disulfide bonds with Cys813 residues located between TM5 and TM6 loops and a Cys892 located between the TM7 and TM8 loops on the α subunit of the H+/K+-ATPase(5) [17].

== Drug-Molecule Interaction ==

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 == Esomeprazole Mechanism ==
-Esomeprazole is protonated twice within the acidic environment, and forms the active inhibitor—achiral sulfenamide at pKa of 1.0 [15]. [[Image:mechanism of inhibition.jpg|500px|right|thumb| '''Activation of Esomeprazole to sulfonamide [7].''' R1=OCH3, R2=CH3, R3=CH3, R4=CH3, X=CH, Bz=benzimidazole, Py=pyridine[7]. Mechanism: (1) protonation of Py, (2) protonation of Bz, (3) intramolecular rearrangement of BzH+-Py, forms sulfenic acid (4) dehydration to form sulfenamide (5) disulfide bond formation between enzyme Cys residues and sulfenamide. ]] The mechanism by which Esomeprazole is converted is as follows: the pyridine ring is first protonated (1), which alters the configuration of the enzyme to the E2 form. Esomeprazole accumulates in the stimulated secretory canaliculus of the parietal cell. As H+ is being transported by the ATPase, the second H+ is added onto the benzimidazole moiety (2) [7]. The bis-protonated forms are in equilibrium with the unprotonated pyridine and protonated benzimidazole rings [7].The protonated benzimidazole ring reacts with the unprotonated pyridine moiety enabling intramolecular rearrangement, resulting in a tetracyclic sulfenic acid (3) [7]. The sulfenic acid is dehydrated to form an active sulfenamide; both are thiophilic agents that are permanently cationic and membrane impermeable (4) [16]. Sulfenamide can form disulfide bonds with Cys813 residues located between TM5 and TM6 loops and a Cys892 located between the TM7 and TM8 loops on the α subunit of the H+/K+-ATPase(5) [17].
+Esomeprazole is protonated twice within the acidic environment, and forms the active inhibitor—achiral sulfenamide at pKa of 1.0 [15]. [[Image:mechanism of inhibition.jpg|500px|right|thumb| '''Activation of Esomeprazole to sulfonamide [7].''' R1=OCH3, R2=CH3, R3=CH3, R4=CH3, X=CH, Bz=benzimidazole, Py=pyridine[7]. Mechanism: (1) protonation of Py, (2) protonation of Bz, (3) intramolecular rearrangement of BzH+-Py, forms sulfenic acid (4) dehydration to form sulfenamide (5) disulfide bond formation between enzyme Cys residues and sulfonamide [7]. ]] The mechanism by which Esomeprazole is converted is as follows: the pyridine ring is first protonated (1), which alters the configuration of the enzyme to the E2 form. Esomeprazole accumulates in the stimulated secretory canaliculus of the parietal cell. As H+ is being transported by the ATPase, the second H+ is added onto the benzimidazole moiety (2) [7]. The bis-protonated forms are in equilibrium with the unprotonated pyridine and protonated benzimidazole rings [7].The protonated benzimidazole ring reacts with the unprotonated pyridine moiety enabling intramolecular rearrangement, resulting in a tetracyclic sulfenic acid (3) [7]. The sulfenic acid is dehydrated to form an active sulfenamide; both are thiophilic agents that are permanently cationic and membrane impermeable (4) [16]. Sulfenamide can form disulfide bonds with Cys813 residues located between TM5 and TM6 loops and a Cys892 located between the TM7 and TM8 loops on the α subunit of the H+/K+-ATPase(5) [17].
 == Drug-Molecule Interaction ==